Biomolecules of Fermented Tropical Fruits and Fermenting Microbes as Regulators of Human Hair Loss, Hair Quality, and Scalp Microbiota.

Plant-derived secondary metabolites (polyphenols/terpenes/alkaloids) and microbial exometabolites/membrane components of fermented tropical fruits are known as highly bioavailable biomolecules causing skin and hair improvement effects (wound healing, anti-inflammatory, antioxidant, antidiabetic, antiacne, skin/hair microbiota balancing, hair growth-promoting, and hair loss-inhibiting). Caffein is considered as a hair growth promoter. A randomized placebo- and caffein-controlled clinical trial on the efficacy of fermented papaya (FP) plus fermented mangosteen (FM) towards human hair quality and loss was conducted. Shampoo and lotion hair care products containing FP, FM, and caffein as active agents were developed and applied to 154 subjects of both sexes with clinically confirmed androgenic or diffuse alopecia for 3 months. Their clinical efficacy was assessed subjectively by questionnaires filled in by dermatologists/trichologists, and by the objective trichomicroscopical calculations. Hair and scalp skin quality was determined by microbiota pattern and ATP, SH-groups, protein, and malonyl dialdehyde quantification. Comparative clinical data showed that the experimental hair care cosmetics significantly inhibited hair loss, increased hair density/thickness, and improved hair follicle structure versus placebo and caffein controls. The cosmetics with FP and FM substantially normalized the microbiota pattern and increased ATP content in hair follicle, while inhibiting lipid peroxidation in the scalp skin, and SH-group formation in the hair shaft.

Fermented Mangosteen (Garcinia mangostana L.) Supplementation in the Prevention of HPV-Induced Cervical Cancer: From Mechanisms to Clinical Outcomes.

In the observational clinical study, we identified the oxidative markers of HPV-associated cervical carcinogenesis and the local/circulating ligands of TNF-alpha-induced apoptosis. Cervical biopsies of 196 females infected with low-cancer-risk HPV10/13 or high-cancer-risk HPV16/18 (healthy, pre-cancerous CIN I and CIN II, and CIN III carcinoma) were analysed for OH radical scavenging, catalase, GSH-peroxidase, myeloperoxidase (MPO), nitrate/nitrite, nitrotyrosine, and isoprostane. Ligands of TNF-alpha-dependent apoptosis (TNF-alpha, TRAIL, IL-2, and sFAS) were determined in cervical fluid, biopsies, and serum. Cervical MPO was highly enhanced, while nitrotyrosine decreased in CIN III. Local/circulating TRAIL was remarkably decreased, and higher-than-control serum TNF-alpha and IL-2 levels were found in the CIN I and CIN III groups. Then, 250 females infected with HPV16/18 (healthy and with CIN I and CIN II) were recruited into a placebo-controlled clinical study of supplementation with fermented mangosteen (FM, 28g/day, daily) for three months. Post-trial colposcopy revealed normal patterns in 100% of the FM group versus 62% of the placebo group. Inflammatory cells in cervical fluid were found in 21% of the FM group versus 40% of the placebo group. Locally, FM drastically diminished MPO and NO2/NO3, while it remarkably increased TRAIL. Additionally, FM supplementation normalised serum TRAIL, TNF-alpha, and IL-2.

Fermented Carica papaya and Morinda citrifolia as Perspective Food Supplements for the Treatment of Post-COVID Symptoms: Randomized Placebo-Controlled Clinical Laboratory Study.

Food supplements based on fermented Carica papaya and Morinda citrifolia, known for their immune modulating, redox balancing, and anti-inflammatory effects, were added to conventional treatment protocols prescribed to patients recovering after severe and moderate COVID-19 disease in order to alleviate long-lasting post-COVID symptoms. A randomized single-center placebo-controlled clinical laboratory study was designed and performed (total number of participants 188, with delta variant of virus 157, with omicron 31). Clinical statuses were assessed using computer tomography, electrocardiography, a questionnaire, and physical endurance. Plasma cytokines (IL-6, IL-8, IL-17A, and INF-gamma), nitrate/nitrite ratio, antioxidant activity (AOA), and polymorphonuclear leukocyte (PMN) ATP levels were determined before and 20 days following the addition of 28 g of fermented supplements twice per day. The capacity of PMN to phagocyte and the oral-nasal-pharyngeal microbiota were assessed. Clinical symptoms, IL-6, IL-8, and nitric oxide metabolites diminished significantly compared to the placebo group and their background expression. The PMN capacity to phagocyte, AOA, and ATP content remarkably increased. The oral-nasal-pharyngeal microbiota were unchanged. On these grounds, we suggest that fermented tropical fruits could efficiently diminish post-COVID clinical symptoms through several immune-modulating, redox balancing, and pro-energy mechanisms.

Influence of the SOD2 A16V gene polymorphism on alterations of redox markers and erythrocyte membrane fatty acid profiles in patients with multiple chemical sensitivity.

Chronically increased oxidative stress has been reported in patients with multiple chemical sensitivity (MCS). Recently, a single nucleotide polymorphism of the gene coding for mitochondrial superoxide dismutase (SOD2), namely the missense substitution A16V (C47>T) resulting in alteration of SOD2 enzyme activity, has been reported to be associated with MCS. However, the influence of SOD2 A16V genetic background on redox status of patients with MCS has not yet been investigated. Here, the results of a retrospective analysis aimed to evaluate the role of the SOD2 A16V polymorphism in the alterations of antioxidant defense markers as well as fatty acid (FA) composition of erythrocyte membranes in 67 patients with MCS matched with 55 healthy controls is reported. The mutated SOD2 V16 variant was observed more frequently in the MCS group compared with the control group, and this difference was statistically significant. The most common genotype in both groups was the heterozygous SOD2 AV16 variant, whereas the mutated SOD2 VV16 variant was more frequently observed in the MCS group, although the difference was not significant. The MCS cohort showed significantly depleted levels of plasma total antioxidant activity, ubiquinol, erythrocyte reduced glutathione and membrane polyunsaturated FA levels, coupled with significant increases in glutathione peroxidase activity, likely accounting for sustained detoxification from lipoperoxides. Notably, the highest levels of oxidative stress were found in patients with MCS bearing the genotype SOD2 AA16, whereas intermediate levels were found in patients bearing the heterozygous AV16 genotype. Healthy subjects bearing the SOD2 AA16 genotype also showed increased oxidative stress compared with carriers of other SOD2 genotypes. Despite the need for further confirmations in larger cohorts, due to MCS population genetic heterogeneity, these preliminary findings suggest that SOD2 defective activity makes certain patients with MCS more susceptible to developing oxidative stress following a chronic daily exposure to pro-oxidant insults.

Effects of Heavy Isotopes (2H1 and 18O16) Depleted Water Con-Sumption on Physical Recovery and Metabolic and Immunological Parameters of Healthy Volunteers under Regular Fitness Load.

Water depleted of heavy isotopes, such as 2H1 and 18O16 (HIDW), has shown numerous biological/health effects in vitro, in vivo, and in epidemiological studies. Major observations were related to cell growth/differentiation, immune/nervous system responses, endurance/adaptation, mitochondrial electron transfer, energy production, glucose metabolism, etc. No human studies to confirm physiological, metabolic, and immune responses to the consumption of HIDW have been performed. A placebo-controlled study on healthy volunteers (n = 50) under fitness load who consumed 1.5 L HIDW (58 ppm 2H and 1780 ppm 18O) or normal water for 60 days was carried out. Plasma content of 2H1 and 18O16, markers of energy, lipid, and glucose metabolism, anthropometric, cardio-vascular, oxidant/antioxidant, and immunological parameters were determined. Significant decrease in plasma heavy isotopes in the group consuming HIDW was observed in concomitance with an increase in ATP, insulin, and LDH, and diminished plasma lactate. Several anthropometric and cardio-vascular parameters were improved as compared to placebo group. Lipid markers demonstrated antiatherogenic effects, while oxidant/antioxidant parameters revealed HIDW-induced hormesis. Antibacterial/antiviral immunity was remarkably higher in HIDW versus placebo group. Conclusions: HIDW consumption by humans under fitness load could be a valid approach to improve their adaptation/recovery through several mechanisms.

The SNP rs2298383 Reduces ADORA2A Gene Transcription and Positively Associates with Cytokine Production by Peripheral Blood Mononuclear Cells in Patients with Multiple Chemical Sensitivity.

Systemic inflammation and immune activation are striking features of multiple chemical sensitivity (MCS). The rs2298383 SNP of ADORA2A gene, coding for adenosine receptor type 2A (A2AR), has been involved in aberrant immune activation. Here we aimed to assess the prevalence of this SNP in 279 MCS patients and 238 healthy subjects, and its influence on ADORA2A, IFNG and IL4 transcript amounts in peripheral blood mononuclear cells of randomly selected patients (n = 70) and controls (n = 66) having different ADORA2A genotypes. The ADORA2A rs2298383 TT mutated genotype, significantly more frequent in MCS patients than in controls, was associated with a three-fold increased risk for MCS (O.R. = 2.86; C.I. 95% 1.99-4.12, p < 0.0001), while the CT genotype, highly prevalent among controls, resulted to be protective (O.R. = 0.33; C.I. 95% 0.224-0.475, p < 0.0001). Notably, ADORA2A mRNA levels were significantly lower, while IFNG, but not IL4, mRNA levels were significantly higher in TT MCS patients compared with controls. A significant negative correlation was found between ADORA2A and both IFNG and IL4, while a significant positive correlation was found between IFNG and IL4. These findings suggest that A2AR defective signaling may play a relevant role in PBMC shift towards a pro-inflammatory phenotype in MCS patients.

Anti-Bacterial and Anti-Inflammatory Effects of Toothpaste with Swiss Medicinal Herbs towards Patients Suffering from Gingivitis and Initial Stage of Periodontitis: from Clinical Efficacy to Mechanisms.

OBJECTIVE: To distinguish clinical effects and mechanisms of sodium monofluorophosphate plus xylitol and herbal extracts of Swiss medicinal plants (Chamomilla recutita, Arnica montana, Echinacea purpurea, and Salvia officinalis). MATERIALS AND METHODS: A 2-month-long comparative clinical study of toothpaste containing 1450 ppm sodium monofluorophosphate and xylitol (control, 15 patients) and toothpaste additionally containing extracts of the medicinal herbs (experiment, 35 patients) was performed on patients with gingivitis and the initial stage of periodontitis. Clinical indices of gingivitis/periodontitis were quantified by Loe & Silness's, CPITN, OHI-S, and PMA indexes. The pro-inflammatory and anti-inflammatory interleukins, nitrites/nitrates, total antioxidant activity, and bacterial pattern characteristic for gingivitis and periodontitis were quantified in the gingival crevicular fluid and plaque. In the in vitro tests, direct anti-bacterial effects, inhibition of catalase induction in Staphylococcus aureus, in response to oxidative burst of phagocytes, and intracellular bacterial killing were determined for the toothpastes, individual plant extracts, and their mixture. RESULTS: Experimental toothpaste was more efficient clinically and in the diminishing of bacterial load specific for gingivitis/periodontitis. Although the control toothpaste exerted a direct moderate anti-bacterial effect, herbal extracts provided anti-inflammatory, anti-oxidant, direct, and indirect anti-bacterial actions through inhibition of bacterial defence against phagocytes. CONCLUSIONS: Chemical and plant-derived anti-bacterials to treat gingivitis and periodontitis at the initial stage should be used in combination amid their different mechanisms of action. Plant-derived actives for oral care could substitute toxic chemicals due to multiple modes of positive effects.

Natural Substances for Prevention of Skin Photoaging: Screening Systems in the Development of Sunscreen and Rejuvenation Cosmetics.

Solar broadband UV irradiation is commonly regarded as a major causative reason for cutaneous photoaging. The pro-aging molecular pathways and cellular targets affected by UVA+UVB light in human skin have been extensively investigated. Notwithstanding growing knowledge in mechanisms of photoaging, research and development of clinically efficient, nontoxic, and sustainable topical preparations providing full physical, chemical, and biological photoprotection still remain a great challenge for pharmaceutical and cosmetic industries. In this study, we are proposing a panel of the in vitro methods for preselection of natural photoprotective substances with high photostability and low phototoxicity able of absorbing a broadband UVA+UVB irradiation (physical sunscreen), reducing UV-related overproduction of free radicals and loss of endogenous antioxidants (chemical protection), and attenuating UV-induced cytotoxicity and immune and metabolic responses (biological protection) in primary human epidermal keratinocytes and immortalized human keratinocyte cultures. Our data showed that secondary metabolites biosynthesized in plant cells in response to UV irradiation, such as phenylpropanoids and their glycosylated metabolites, aglycons and glycosylated flavonoids, and leontopodic acids, hold the best promise for complete natural topical prevention of photoaging and rejuvenation of photoaged skin. Meristem plant cell cultures elicited by solar simulating UV could be the most environmentally sustainable biotechnological source of polyphenols with combined photoprotective and antiaging properties.

Meristem Plant Cells as a Sustainable Source of Redox Actives for Skin Rejuvenation.

Recently, aggressive advertisement claimed a "magic role" for plant stem cells in human skin rejuvenation. This review aims to shed light on the scientific background suggesting feasibility of using plant cells as a basis of anti-age cosmetics. When meristem cell cultures obtained from medicinal plants are exposed to appropriate elicitors/stressors (ultraviolet, ultrasound ultraviolet (UV), ultrasonic waves, microbial/insect metabolites, heavy metals, organic toxins, nutrient deprivation, etc.), a protective/adaptive response initiates the biosynthesis of secondary metabolites. Highly bioavailable and biocompatible to human cells, low-molecular weight plant secondary metabolites share structural/functional similarities with human non-protein regulatory hormones, neurotransmitters, pigments, polyamines, amino-/fatty acids. Their redox-regulated biosynthesis triggers in turn plant cell antioxidant and detoxification molecular mechanisms resembling human cell pathways. Easily isolated in relatively large quantities from contaminant-free cell cultures, plant metabolites target skin ageing mechanisms, above all redox imbalance. Perfect modulators of cutaneous oxidative state via direct/indirect antioxidant action, free radical scavenging, UV protection, and transition-metal chelation, they are ideal candidates to restore photochemical/redox/immune/metabolic barriers, gradually deteriorating in the ageing skin. The industrial production of plant meristem cell metabolites is toxicologically and ecologically sustainable for fully "biological" anti-age cosmetics.

Effects of Standardised Fermented Papaya Gel on Clinical Symptoms, Inflammatory Cytokines, and Nitric Oxide Metabolites in Patients with Chronic Periodontitis: An Open Randomised Clinical Study.

The clinical efficacy of topical administration of standardised fermented papaya gel (SFPG), known to have antioxidant and anti-inflammatory properties, versus conventional therapy was evaluated in a group of 84 patients with moderate-to-severe periodontitis, randomly assigned to control group (n = 45) undergoing traditional pharmacologic/surgical protocols or to experimental group (n = 39), additionally treated with intragingival pocket SFPG (7 g) applications (15 min daily for 10 days). Patients undergoing SFPG treatment showed significant (P < 0.05), durable improvement of three major clinical indices of disease severity: reduced bleeding (day 7), plaque and gingival conditions (day 14), and consistent gingival pocket depth reduction (day 45). Proinflammatory nitric oxide metabolites reached normal values in plasma (day 14) and gingival crevicular fluid (GCF) at day 45 with SFPG applications compared to controls that did not reach normalisation. Levels of highly increased proinflammatory (IL-1B, IL-6) and suppressed anti-inflammatory (IL-10) cytokines normalised in the SFPG group by days 14 (plasma) and 45 (GCF), but never in the control group. Although not acting directly as antibiotic, SFPG acted in synergy with human granulocytes blocking adaptive catalase induction in S. aureus in response to granulocyte-derived oxidative stress, thus enhancing intracellular bacterial killing.

Skin Antiageing and Systemic Redox Effects of Supplementation with Marine Collagen Peptides and Plant-Derived Antioxidants: A Single-Blind Case-Control Clinical Study.

Recently, development and research of nutraceuticals based on marine collagen peptides (MCPs) have been growing due to their high homology with human collagens, safety, bioavailability through gut, and numerous bioactivities. The major concern regarding safety of MCPs intake relates to increased risk of oxidative stress connected with collagen synthesis (likewise in fibrosis) and to ROS production by MCPs-stimulated phagocytes. In this clinical-laboratory study, fish skin MCPs combined with plant-derived skin-targeting antioxidants (AO) (coenzyme Q10 + grape-skin extract + luteolin + selenium) were administered to volunteers (n = 41). Skin properties (moisture, elasticity, sebum production, and biological age) and ultrasonic markers (epidermal/dermal thickness and acoustic density) were measured thrice (2 months before treatment and before and after cessation of 2-month oral intake). The supplementation remarkably improved skin elasticity, sebum production, and dermal ultrasonic markers. Metabolic data showed significant increase of plasma hydroxyproline and ATP storage in erythrocytes. Redox parameters, GSH/coenzyme Q10 content, and GPx/GST activities were unchanged, while NO and MDA were moderately increased within, however, normal range of values. Conclusions. A combination of MCPs with skin-targeting AOs could be effective and safe supplement to improve skin properties without risk of oxidative damage.

Metabolic and redox barriers in the skin exposed to drugs and xenobiotics.

INTRODUCTION: Growing exposure of human skin to environmental and occupational hazards, to numerous skin care/beauty products, and to topical drugs led to a biomedical concern regarding sustainability of cutaneous chemical defence that is essential for protection against intoxication. Since skin is the largest extra-hepatic drug/xenobiotic metabolising organ where redox-dependent metabolic pathways prevail, in this review, publications on metabolic processes leading to redox imbalance (oxidative stress) and its autocrine/endocrine impact to cutaneous drug/xenobiotic metabolism were scrutinised. AREAS COVERED: Chemical and photo-chemical skin barriers contain metabolic and redox compartments: their protective and homeostatic functions. The review will examine the striking similarity of adaptive responses to exogenous chemical/photo-chemical stressors and endogenous toxins in cutaneous metabolic and redox system; the role(s) of xenobiotics/drugs and phase II enzymes in the endogenous antioxidant defence and maintenance of redox balance; redox regulation of interactions between metabolic and inflammatory responses in skin cells; skin diseases sharing metabolic and redox problems (contact dermatitis, lupus erythematosus, and vitiligo) EXPERT OPINION: Due to exceptional the redox dependence of cutaneous metabolic pathways and interaction of redox active metabolites/exogenous antioxidants with drug/xenobiotic metabolism, metabolic tests of topical xenobiotics/drugs should be combined with appropriate redox analyses and performed on 3D human skin models.

Redox Control of Multidrug Resistance and Its Possible Modulation by Antioxidants.

Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic enzymes with a temporal redox-regulated axis. This results in rapid metabolic transformation and elimination of a toxin. This metabolic axis is tightly interconnected with the inducible Nrf2-linked pathway, a key switch-on mechanism for upregulation of endogenous antioxidant enzymes and detoxifying systems. As a result, chemotherapeutics and cytotoxic by-products of their metabolism (ROS, hydroperoxides, and aldehydes) are inactivated and MDR occurs. On the other hand, tumour cells are capable of mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells. The multiple redox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) or inhibitors of inducible antioxidant defence as a novel approach to diminish MDR. Pitfalls and progress in this direction are discussed.

Integrated Haematological Profiles of Redox Status, Lipid, and Inflammatory Protein Biomarkers in Benign Obesity and Unhealthy Obesity with Metabolic Syndrome.

The pathogenesis of obesity (OB) and metabolic syndrome (MetS) implies free radical-, oxidized lipid- (LOOH-), and inflammatory cytokine-mediated altered pathways in target organs. Key elements of the transition from benign OB to unhealthy OB+MetS remain unclear. Here, we measured a panel of redox, antioxidant, and inflammation markers in the groups of OB patients (67 with, 45 without MetS) and 90 controls. Both OB groups displayed elevated levels of adipokines and heavy oxidative stress (OS) evidenced by reduced levels of glutathione, downregulated glutathione-S-transferase, increased 4-hydroxynonenal-protein adducts, reactive oxygen species, and membrane-bound monounsaturated fatty acids (MUFA). Exclusively in OB+MetS, higher-than-normal glutathione peroxidase activity, tumor necrosis factor-α, and other proinflammatory cytokines/chemokines/growth factors were observed; a combination of high adipokine plasminogen activator inhibitor-1 and MUFA was consistent with increased cardiovascular risk. The uncomplicated OB group showed features of adaptation to OS such as decreased levels of vitamin E, activated superoxide dismutase, and inhibited catalase, suggesting H2O2 hyperproduction. Proinflammatory cytokine pattern was normal, except few markers like RANTES, a suitable candidate for therapeutic approaches to prevent a setting of MetS by inhibition of LOOH-primed leukocyte chemotaxis/recruitment to target tissues.

Is there a role for antioxidants in the prevention of infection-associated carcinogenesis and in the treatment of infection-driven tumors?

Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen-centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/ aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL-related apoptosis and the induction of intracellular oxidative stress.

Is there a Role For Antioxidants in the Prevention of Infection-Associated Carcinogenesis and in the Treatment of Infection-Driven Tumors?

Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen-centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL-related apoptosis and the induction of intracellular oxidative stress.

Verbascoside--a review of its occurrence, (bio)synthesis and pharmacological significance.

Phenylethanoid glycosides are naturally occurring water-soluble compounds with remarkable biological properties that are widely distributed in the plant kingdom. Verbascoside is a phenylethanoid glycoside that was first isolated from mullein but is also found in several other plant species. It has also been produced by in vitro plant culture systems, including genetically transformed roots (so-called 'hairy roots'). Verbascoside is hydrophilic in nature and possesses pharmacologically beneficial activities for human health, including antioxidant, anti-inflammatory and antineoplastic properties in addition to numerous wound-healing and neuroprotective properties. Recent advances with regard to the distribution, (bio)synthesis and bioproduction of verbascoside are summarised in this review. We also discuss its prominent pharmacological properties and outline future perspectives for its potential application.